Trialkylsilyl ethers of 17alpha-alkynylestra - 1,3,5(10) - triene-3,17beta-diols and 11beta-alkyl derivatives thereof

ABSTRACT

THE REACTION OF 17A-ALKYNYLESTRA-1,3,5(10)-TRIENE-3, 17B-DIOLS, OPTIONALLY ALKYATED AT TE 11-POSITION, WITH A TRIALKYLSILYL CHLORIDE AFFORDS THE CORRESPONDING TRIALKYLSILYL ETHERS, WHICH ARE USEFUL PHARMACOLOGICAL AGENTS AS EVIDENCED BY THEIR POTENT AND LONG-ACTING ESTROGENIC AND ANTI-FERTILITY PROPERTIES.

United States Patent 3,755,384 TRIALKYLSILYL ETHERS F 17OL'ALKYNYL- ESTRA 1,3,5() TRIENE-3,17,S-DIOLS AND llfi-ALKYL DERIVATIVES THEREOF Edward A. Brown, Wilmette, and Ivar Laos, Skokie, Ill., assignors to G. D. Searle & Co., Chicago, Ill. No Drawing. Filed Apr. 7, 1971, Ser. No. 132,152 Int. Cl. C07c 169/08 U.S. Cl. 260-3975 6 Claims ABSTRACT OF THE DISCLOSURE The reaction of l7u-alkynylestra-1,3,5(10)-triene-3, 17fl-diols, optionally alkyated at te ll-position, with a trialkylsilyl chloride affords the corresponding trialkylsilyl ethers, which are useful pharmacological agents as evidenced by their potent and long-acting estrogenic and anti-fertility properties.

The present invention is concerned with steroidal silyl ethers and, more particularly, with trialkylsilyl ethers of l7m-alkynylestra-l,3,5 (10)-triene-3,l75-diols and the 11,8- alkyl derivatives thereof. These compounds are represented by the following structural formula CH? --(1ower alkynyl) wherein R can be either hydrogen or a tri-(lower alkyl) silyl group and R denotes hydrogen or an alkyl radical containing less than four carbon atoms.

The lower alkyl radicals encompassed in the foregoing structural formula are typified by methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and the branched-chain isomers thereof.

Representative of the lower alkynyl groups, denoted in that formula are ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl and the branched-chain radicals isomeric therewith.

The compounds of the present invention are conveniently manufactured by contacting a 3,17,8-diol of the following structural formula (lower alkynyl) afford 17a-ethynyl 17,8 hydroxyestra-l,3,5(10)-trien-3- yloxy-(tertiary-butyl)dimethylsilane and the latter derivative is allowed to react with trimethylsilyl chloride and pyridine in the presence of hexamethyldisilazane to produce 17a-ethynyl 17 3 trimethylsilyloxyestra-l,3,5 l0)- trien-3-yloxy-(tertiary-butyl)dimethylsilane.

An alternate procedure for production of the instant bis-silyl ethers, wherein the silyl groups at positions 3 and 17 are identical, consists of contacting the aforementioned 3,17B-diol starting materials with a tri-(lower al'kyl)silyl chloride in the presence of the corresponding hexaalkyldisilazane. 17u-ethynyl-ld/i-methyl-Ufl-trimethylsilyloxyestra 1,3,5(1()) trien-3-yloxytrimethylsilane is thus produced when l7u-ethynyl-1lfl-methylestra-L3, 5(10)-triene-3,17.13-diol is contacted with trimethylsilyl chloride and pyridine in the presence of he-xamethyldisilazane.

The compounds of the present invention display valuable pharmacological activity as evidenced by their potent estrogenic and anti-fertility properties. They are particularly advantageous in view of their prolonged action.

The prolonged estrogenic action of these compounds is determined by a method adapted from that originally described by Allen and Doisy, I. Am. Med. Assoc., '81, 819 (:1923). Details of that assay are as follows:

Female rats, 60 days of age, are spayed and allowed to recover for a period of 20-30'days. At 89-90 days of age the rats are primed with two equal injections of 2.5 mcg. of estrone and 0.1 ml. of corn oil, spaced 24 hours apart. The vaginal mucosa is examined 56 and 72 hours after the first injection, and those animals responding positively to two courses of priming are selected for testing purposes. Each test animal is treated with a selected close of the test compound administered in two equal portions given 24 hours apart. Fresh smears are taken from the vaginal mucosa three times per week with 2-3 days between smears and are examined microscopically for the presence of cornified and/or round nucleated epithelial cells. Using that criterion, each smear is scored as positive or negative. A test substance is considered active if positive responses are obtained in more than 10% of the animals. In order to determine the duration of activity, fresh smears are taken until positive responses are no longer observed in more than 10% of the animals.

The anti-fertility property of the compounds of this invention is detected by the following assay:

A group of young adult Charles River female rats is treated with a single dose of the test compound dissolved in corn oil, at which time a control group is treated with corn oil alone. On the day of treatment, each of the treated and control animals is placed together with a male, then is observed until evidence of pregnancy occurs. At that time, the pregnant rat is isolated from the male and is observed until such time as littering occurs. A compound is rated active if the time until littering is significantly increased.

The instant novel compounds are useful also as chemosterilants for the control of nuisance animal populations. Thus, these compounds provide a means for limiting the population of animals which are regarded as pests in various geographic areas of the world. Such nuisance animals, particularly when occurring in large numbers, can present severe economic and health hazards by damaging agricultural crops and trees, household articles and food stuflfs; by killing livestock or desirable wild animals and birds; by competing with more desirable animals for food; by destruction resulting from their burrowing and gnawing; or by transmitting diseases to man and animals. These nuisance animals include opossums of the family di- Delphidae, order Marsupialia; fruit-eating bats and true vampire bats of the order Chiroptera; rabbits and hares of the order Lagamorpha; members of the order Carnivora such as coyotes, blackbacked iackals, foxes, wolves, tayras, grisons, honey badgers, American badgers, mongooses and pumas; certain species of ungulates of the family Suidae; and, most particularly, mammals of the order Rodentia, for example ground and tree squirrels, marmots, prairie dogs, pocket gophers, tuzas and taltuzas, rice rats, highland desert mice, marsh rats, cotton rats, common hamsters, true lemmings, muskrats, gerbils, mole rats, garden dormice, tree dormice, spinydormice, porcupines, cavies, guinea pigs, nutrias, cane rats, blesmols, sand rats, members of the genus microtus such as meadow mice, and rodents of the family Muridae such as those of the genera Apodemus Millardia, Rattus (especially black rats and Norway rats), Mus (e.g. common house mice), Bandicota and Nesokia.

Representative of the chemosterilant activity of the novel compounds of this invention is their inhibition of the secretion of the pituitary gonadotrophins and consequent inhibition of ovulation and conception in nuisance animals such as rats. Furthermore, these compounds have been found to prevent implantation in newly mated rodents. In addition, fed to rats near the time of parturition, these compounds are excreted in the milk in sufiicient quantities to sterilize the nursing female offspring. Such female rodents, when mature, exhibit nearly con stant estrus but do not ovulate. Furthermore, because wild rodents as well as other nuisance animals, cannot be expected to return with regularity to a single food source, a particularly important advantage of the instant compounds is their long duration of activity upon oral administration. Because of these facts, the compounds of this invention may be used as population control agents for nuisance animals, conveniently by placing them in a bait. The bait comprises one of the compounds of the instant invention and an edible carrier. The term edible carrier signifies all non-toxic substances consumable or ingestable by animals in solid, liquid or other suitable form. The edible carrier can thus, for example, consist of one or more of the following: foods, food additives (e.g. sweeting or flavoring agents), aerosol propellants, fillers, binders, common organic and inorganic solids. When the carrier is a liquid, the bait can be in the form of a solution, suspension, syrup or emulsion. The active ingredient, i.e. one of the compounds of this invention, and the carrier are mixed in a known manner and the bait so prepared is distributed in an area frequented by nuisance animals. Obviously, the bait can itself represent a substitute or supplemental food or drinking supply for the animals or it can be in a form which is to be applied for example by spraying or injection to the crops, trees or articles which the nuisance animals consume or ingest.

For rodents, the edible carrier is preferably a food which rodents find to be highly palatable such as cereal grains, cracked corn, corn meal, bread crumbs, meat or fish scraps, oils such as vegetable or fish oils, powdered sugar, molasses, salt and spices and various mixtures thereof. The bait so prepared is distributed in an area frequented by rodents. For greatest effect on total population it is desirable to administer the material at about the time of parturition so that the female will be sterilized. Thus, single distributions of bait at repeated intervals of 6 weeks are preferred for many rodent species. Obviously, the time intervals will vary according to the reproductive cycle of the particular nuisance animal involved. It is apparent that the concentration of active ingredient can vary considerably depending upon the particular nuisance animal concerned and the specific edible carrier used.

The invention will appear more fully from the examples which follow. These examples are given by way of illustration only and are not to be construed as limiting the invention either in spirit or in scope as many modifications both in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples, temperatures are given in degrees centigrade 4 C.) and quantities of materials in parts by weight unless otherwise noted.

EXAMPLE 1 To a solution of 17a-ethynylestra-1,3,5(10)-triene-3, 17,8-diol in 5 parts of pyridine is added 1 part of (tertiarybutyl)dimethylsilyl chloride. After standing at a temperature of about for approximately 18 hours, the precipitated pyridine hydrochloride is removed by filtration and the filtrate is poured into approximately 100 parts of a mixture of ice and water. Extraction of that aqueous mixture with hexane aifords an organic solution, which is washed with Water, then dried over anhydrous sodium sulfate. Distillation of the solvent under reduced pressure affords a residue which crystallizes upon standing. Recrystallization of that crude product from hexane yields 17aethynyl-l7B-hydroxyestra-1,3,5(l0)-trien 3 yloxy-(tertiary-butyl)dimethylsilane melting at about 120. This compound is represented by the following structural formula Hs)s i0 EXAMPLE 2 When an equivalent quantity of 17a-butynylestra-1,3,5

' (10)-triene-3,17B-diol is substituted in the procedure of Example 1, there is produced 17a-butynyl-l7fl-hydroxyestra 1,3,5(10) trien 3 yloxy-(tertiary-butyl)dimethylsilane.

EXAMPLE 3 The substitution of an equivalent quantity of ethylmethylpropylsilyl chloride in the procedure of Example 1 results in 17u-ethynyl-17 3-hydroxyestra-1,3,5(l0)-trien- 3-yloxyethylmethylpropyl silane.

EXAMPLE 4 To a solution of 1.05 parts of 17a-ethynyl-11e-methylestra 1,3,5(10) triene 3,17,6-dio1 in '5 parts of pyridine is added 1 part of (tertiary-butyl)dimethylsilyl chloride I and that reaction mixture is stored at 3035 for about 16 hours. The crude product is precipitated by pouring into a mixture of ice and water, then is isolated by filtration. Further purification is 'efiected by dissolution in a 3:1 mixture of hexane andbenzene, followed by washing of that organic solution with water, drying over anhydrous EXAMPLE 5 By substituting an equivalent quantity of llfl methylpropynylestra 1,3,5 (10) triene-3,17fi-diol and ""CEOH otherwise proceeding according to the processes described in Example 4, there is obtained 17,8-hydroxy-11B-methyl- 17a. propynylestra 1,3,5(l) trien-3-yloxy-(tertiarybutyl)dimethylsilane.

EXAMPLE 6 The reaction of 1113 methyl-17a-propynylestra-1,3,5- (10 tn'ene 3,17/3 diol with ethylmethylpropylsilyl chloride according to the procedure described in Example 4 results in l7fi-hydroxy-1lB-methyl-l7a-propynylestral,3,5(10) trien 3 yloxyethylmethylpropylsilane.

EXAMPLE 7 A mixture containing 0.8 part of 17a-ethynyl-17fi-hydroxyestra 1,3,5 (10) trien 3 yloxy (tertiary-butyl) dimethylsilane, 5 parts by volume of trimethylsilyl chloride, 80 parts of pyridine and 8 parts by volume of hexamethyldisilazane is kept at room temperature for about 2% hours, then is poured carefully into approximately 500 parts of an ice-water mixture. The resulting precipitate is collected by filtration, then washed with water and dried to afford l7a-ethynyl-17,8-trimethylsilyloxyestra-l, 3,5() trien 3 yloxy (tertiary-butyDdimeth'ylsilane. This compound exhibits infrared maxima, in chloroform, at about 1492, 1568, 1607 and 3310 reciprocal centimeters and also nuclear magnetic resonance peaks in deuterochloroform at about 10, 49, 58 and 153 cycles per second, using a 60 megahertz instrument. It is represented by the following structural formula r (CHa)3CSiO EXAMPLE 8 The substitution of an equivalent quantity of 170:- butynyl 17,8 hydroxyestra 1,3,5(l0) trien 3-yloxy- (tertiary-butyl)dimethylsilane in the procedure of Example 7 results in l7u-butynyl-17B-t1imethylsilyloxyestra- 1,3,5(10) trien '3 yloxy-(tertiary-butyl)dimethylsilane.

EXAMPLE 9 When an equivalent quantity of 17ot-ethynyl-17 3-hydroxyestra 1,3,5(l0) trien 3 yloxyethylmethylpropylsilane is substituted in the procedure of Example 7, there is produced 17a-ethynyl-17p-trimethylsilyloxyestra- *1,3,5(10)-trien-3-yloxyethylmethylpropylsilane.

EXAMPLE 10 When equivalent quantities of ethylmethylpropylsilyl chloride and 1,3 diethyl 1,3-dimethyl-1,3-dipropyldisilazane substituted in the procedure of Example 7, there is obtained 17a ethynyl 17B ethylmethylpropylsilyloxyestra 1,3,5 (10) trien 3 yloxy (tertiary-butyl) dimethylsilane.

EXAMPLE 11 A mixture containing 10 parts of 3,11,8-dihydroxyestra- 1,3,5(l0) trien 17 one 17-ethylene ketal, 112 parts of ethanol, 4.22 parts of benzyl chloride and 8.5 parts of anhydrous potassium carbonate is heated at the reflux temperature for about hours, then is cooled and filtered. The resulting filtrate is concentrated to dryness under reduced pressure and the residual oily crude product is triturated with ether to afford crystals of 3-benzyloxy 11B hydroxyestra 1,3,5(10) trien 17 one 17- ethylene ketal.

To a solution of 1.62 parts of 3-benzyloxy-1lB-hydroxyestra 1,3,5 l0) trien l7 one 17-ethy1ene ketal in parts of acetone is added, at 5-10 over a period of about 2 minutes with vigorous stirring, 1.3 parts of an aqueous solution, 8 N in chromium trioxide and 8 N in sulfuric acid. The excess reagent is destroyed by the addition of a small quantity of isopropyl alcohol and the resulting mixture is filtered through diatomaceous earth, then stirred with approximately 100 parts by volume of saturated sodium bicarbonate. The organic solvent is removed by distillation under reduced pressure and the residual mixture is extracted thoroughly with chloroform. The chloroform extracts are combined, dried over anhydrous magnesium sulfate and concentrated to dryness, thus producing 3-benzyloxyestra-l,3,5 l0)-triene-1 1,17- dione 17-ethylene-ketal.

To a solution of 16.8 parts of 3-benzyloxyestra-l,3,5- (10)triene-ll,17-dione 17-ethylene ketal in 1232 parts of dry benzene, under a nitrogen atmosphere, is added dropwise with stirring 60 parts by volume of 3 M ethereal ethyl magnesium bromide. The reaction mixture is kept slightly below room temperature during addition of the reagent. Stirring is continued for about 20 minutes, at the end of which time the mixture is cooled and 6.2 parts of methanol is added in order to decompose the Grignard adduct. This reaction sequence is then repeated by adding a fresh part by volume portion of ethereal 3 M ethyl magnesium bromide. Stirring at room temperature is continued for about 30 minutes, at the end of which time 10.8 parts of methanol is added. A third addition of Grignard reagent, this time 200 parts by volume of 3 M ethyl magnesium bromide, is carried out and after stirring for one hour, the mixture is diluted with ether and sulficient saturated aqueous ammonium chloride is added to completely precipitate the magnesium salts. The organic layer is decanted from the gummy precipitate and is dried over anhydrous magnesium sulfate, then distilled to dryness under reduced pressure. Purification of the crude product is effected by chromatography on neutral silica followed by elution with benzene-ethyl acetate solutions. The 5% ethyl acetate in benzene eluate is distilled to dryness under reduced pressure, thus affording 3-benzyloxy-llfl-ethyld1a-hydroxyestra-1,3,5(10)-trien 17 one l7-ethylene ketal.

A mixture containing 4.87 parts of 3-benzyloxy-11B- ethyl-l1a-hydroxyestra-1,3,5(l0)-trien-17-one 17 ethylene ketal, 24 parts of concentrated hydrochloric acid and parts of ethanol is heated at the reflux temperature under nitrogen for about 2 /2 hours. The solvent is removed by distillation under reduced pressure and the residual gummy product is extracted into benzene. The benzene extract is Washed successively with aqueous sodium bicarbonate and water, then dried over anhydrous sodium sulfate. Removal of the solvent by distillation under reduced pressure aflords 3-benZyloxy-1l-ethylestra- 1,3,5(10),9(11)-tetraen-17-one, characterized by an infrared absorption peak, in chloroform, at about 5.74 mlCIOIlS.

A mixture containing 1.5 parts of 3-benzyloxy-l1- ethylestra l,3,5(l0),9(1l) tetraen 17 one in 96 parts of methanol and 0.15 part of 10% palladiumon-carbon catalyst is shaken with hydrogene at room temperature and atmospheric pressure until two molecular equivalents of hydrogen have been absorbed. The catalyst is then removed by filtration and the solvent by distillation under reduced pressure. The residual gummy product is purified by chromatography on a neutral silica column and is eluted with ethyl acetatebenzene mixtures. The 1% ethyl acetate in benzene eluate is distilled to dryness under reduced pressure and the resulting crude residue is purified by recrystallization from acetone to afford 3-hydroxy-11B ethylestra 1,3,5 (10)- trien-l7-one, melting at about 269-27l.

A mixture of 4 parts of 11,9-ethyl-3-hydroxyestra-1,3,5- (10)-trien-17-one, 10 parts of 30% lithium acetylide- 70% ethylenediamine complex and 225 parts of tetrahydrofuran is stirred in an acetylene atmosphere at 0.5 for about 2 /2 hours, then is diluted carefully with water. The resulting solution is concentrated to a small volume under nitrogen and the residual mixture is extracted with benzene. The benzene layer is dried over anhydrous magnesium sulfate, then is distilled to dryness under reduced pressure. Trituration of the resulting residue with ether and hexane followed by recrystallization from acetonehexane affords 17ot-ethynyl-l1fi-ethyl 3 hydroxyestra- 1,3,5 (10)-trien-l713-ol.

By substituting an equivalent quantity of llfi-ethyl- 17a-ethynylestra-1,3,5(10)triene-3,l7 3-diol and otherwise proceeding according to the processes described in Example 4, there is obtained lIB-ethyHM-ethynyl 17B hydroxyestra-l,3,5( l) trien 3 yloxy-(tertiary-butyl) dimethylsilane, characterized by the following structural formula EXAMPLE 12 A mixture consisting of 5 parts of 3,17fidihydroxyestra-1,3,5()-trien-1l-one, 2,4 parts of benzyl chloride, 4.8 parts of potassium carbonate and 144 parts of ethanol is heated at the reflux temperature for about 24 hours, hours, then is stripped of solvent by distillation under reduced pressure. The resulting residue is extracted into benzene and the benzene extract is washed with water under reduced pressure atfords the crude product, which until neutral. Removeal of the benzene by distillation is purified by recrystallization from methanol, thus affording 3-benzyloxy-17p hydroxyestra 1,3,5(10) trien ll-one, melting at about 159160.

The reaction of equivalent quantities of 3-benzyloxy- 17fl-hydroxyestra-1,3,S(10)-trien-11-one and ally] magnesium bromide according to the procedure described in Example 11 results in 3-benzyloxy 11 allylestra-1,3,5- (l0)triene-11,17,B-diol, characterized by infrared absorption maxima, in chloroform, at about 2.76, 2.80, 6.04 and 6.11 microns. In deuterochloroform this compound exhibits nuclear magnetic resonance peaks at about 55, 210- 240, 303, 312 and 443 cycles per second using a 60 megahertz instrument.

A mixture containing 4 parts of 11-allyl-3-benzyloxyestra-1,3,5(10)-triene-l1,175-diol and 60 parts by volume of formic acid is heated at steam bath temperature for about 1 hour, at the end of which time approximately 100 parts of water is added. The resulting mixture is filtered and the filtrate is extracted with ether. The ether extract is washed with aqueous sodium bicarbonate until neutral, then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to afford 11-al1yl-3 benzyloxyestra 1,3,5(10),9(l1) tetraen- 17B-0l 17-formate.

A mixture containing 0.6 part of 1I-allyl-3B-benzyloxyestra-1,3,5(10),9(11)-tetraen-l7B-ol l7-formate and 1 part by volume of 6% aqueous potassium hydroxide is stirred at room temperature for about 10 minutes, then is concentrated to dryness under reduced pressure. The resulting residue is extacted with ether and the ether extract is dried over anhydrous sodium sulfate, then concentrated to dryness under reduced pressure, thus afi ording 1l-allylestra-1,3,5(10),9(l1)-tetraene 3,175 diol 3-benzyl ether.

When an equivalent quantity of 11-allylestra-1,3,5(10), 9(1l)-tetraene-3,17B-diol 3-benzyl ether is oxidized with chromium trioxide according to the procedure of Exam- 8 ple 11, there is produced 1l-allyl-3-hydroxyestra-1,3,5-

(10),9(11)tetraen-l7-one 3-benzyl ether.

A mixture containing 0.6 part of 11-ally1-3-hydroxyestra-1,3,5(10),9(11)-tetraen-17-one 3-benzyl ether, parts of isopropyl alcohol and 0.3 part of 10% palladiumon-carbon catalyst is stirred in a hydrogen atmosphere at about 60 pounds per square inch pressure and at a temperature of about 60 for approximately 48 hours, at the end of which time the mixture is cooled and filtered to remove the catalyst. The resulting filtrate is concentrated to dryness to afford 3-hydroxy-11B-propylestra-1,3,5(10)- trien- 17- one, characterized by ultraviolet absorption maxima at about 278 and 286 millimicrons.

Ethynylation of an equivalent quantity of S-hydroxy- 11;3propylestral,3,5(l0)-trien-l7-one according to the procedure described in Example 11 results in17ot-ethynyl- 11B-propylestra-1,3,5 10)-triene-3,1718-diol. 1

When an equivalent quantity of 17wethynyl-11B-propylestra-1,3,5(10)-triene-3,17fi-diol is substituted in the procedure described in Example 4, there is produced ethynyl hydroxy-llB-propylestra-1,3,5(l0)-trien-3- yloxy- (tertiary-butyl)dimethylsilane.

What is claimed is:

1. A compound of the formula (lower alkyl) (lower alkyD Si-O 2. As in claim 1, a compound of the formula (lower alkynyl) (lower alkyl);Si0

3. As in claim 1, a compound of the formula CH3 egan CH3 (lower alkylhSiO References Cited UNITED STATES PATENTS 1/1967 Baran 260397.5 6/ 1972 Teichmuller et al. 260-397.4

HENRY A. FRENCH, Primary Examiner US. Cl. X.R. 260999 'UNITED STATES PATENT OFFICE CERTIFICATE 0F CORRECTION Patent No. August 28, 1975 5,755,5 Dated Inventofls) Edward A. Brown and Ivar Laos It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line l t, "te" should be the Column 5, line 7, (io-" should be (1o)- Column 6, line 61, "hydrogene" should be hydrogen Column 7, line 51, "2,4" should be 2. L

Column '7, line 55, delete "hours,".

Column 7, lines 56-57, "water under" should be water until neutral. Removal oi the benzene by distillation under Column '7, line 58, delete "until neutral. Removel of the benzene by distillation".

Column 7, line 68, "extacted" should be extracted v Signed and sealed this 16th day of April 19714..

(SEAL) Attest:

C...MARSHALL DANN Attesting Officer RM PO-IOSO (10-69) USCOMM-DC 60376-P69 us GOVERNMENT PRINTING OFFICE: i969 0-366-334 

